Irritant composition comprising n-dihaloacetyl-4-alkylcyclohexylamine

ABSTRACT

Repelling animals with N-dihaloacetylcyclohexylamines of the formula:   WHEREIN R1 is hydrogen or alkyl, R2 is hydrogen or alkyl, X is halogen, and Z is halogen. Typical is N-dichloroacetyl-4-t-butylcyclohexylamine useful for repelling animals.

United States Patent Knowles 51 July 11, 1972 [72] Inventor: Richard N.Knowles, Hockessin, Del.

[73] Assignee: E. l. du Pont de Nemours and Company,

. Wilmington, Del.

[5 1] Int. Cl. A0ln 9/20 [58] Field of Search ..424/320, 325; 260/561[56] References Cited UNITED STATES PATENTS 3,007,786 11/1961 Hamm etal. ..260/S6l 2,852,560 9/1958 Brust ..424/320 Primary Examiner-LelandA. Sebastian Attorney-Herbert W. Larson I ABSTRACT Repelling animalswith N-dihaloacetylcyclohexylamines of the formula:

R; O X MLL 2 CH: I

' H Rr I C H3 wherein R, is hydrogen or alkyl, R is hydrogen or alltyl,X is halogen, and Z is halogen.

Typical is N-dichloroacetyl-4-t-butylcyclohexylamine useful forrepelling animals.

8 Claims, No Drawings IRRITANT COMPOSITION COMPRISING N-DIIIALOACETYL-4-ALKYLCYCLOI-IEXYLAMINE CROSS REFERENCE This applicationis a divisional of my copending application Ser. No. 634,131, filed Apr.2, 1967.

BACKGROUND OF THE INVENTION The following applications relate tocompounds containing cyclohexyl ring structures and having utility asanimal repellants:

Application Ser. Nos. 532,544, filed Mar. 1, 1966, now abandoned574,276, filed Aug. 18, 1966,

574,495,fi1ed Aug. 18, 1966,

574,496, filed Aug. 18, 1966,

574,498, filed Aug. 18, 1966, and

574,499, filed Aug. 18, 1966.

l have now discovered an additional class of compounds containing acyclohexyl ring structure and having utility as animal repellants.

SUMMARY OF THE INVENTION 1 have discovered that animal repellentactivity is shown by the following compounds: R2 X Preferred because ofexcellent animal irritant activity at low rates of application are thosecompounds of formula (1) wherein R is methyl and R is hydrogen.

Particularly preferred because of outstanding animal irritant activityat low rates is N-dichloroacetyl-4-t-butylcyclohexylamine.

UTILITY Compounds of this invention cause potent irritation to animaltissue, particularly to the mucous membranes.

Animals exposed to the above compounds show signs of severe respiratoryirritation. These compounds have two advantages over currently usedanimal repellants such as dried blood for deer, allylisothiocyanate fordogs, zinc dithiocarbamate-amine complex for rodents, and bone tar oilfor deer. One, the compounds are more potent at low concentrations andtwo, provide residual activity over longer periods of time.

Compounds of this invention and particularly cis/trans mixtures ofN-dichloroacetyl-4-t-butylcyclohexyl-amine have potential use as dogrepellants, rodent repellants, deer repellants and for contaminatingcaves or underground tunnels.

PREPARATION on; 0 (E DMAC R1 s NHR2 XZCH o 2 CH3 CH3 R2 0 The acidchloride exemplified in reaction 11 can be replaced by the acid bromideif desired.

The dihaloacetamides are isolated from either the dimethylacetamidesolution or pyridine solution by dumping the solution into 10 to 100times its volume of water. The product initially separates as an oil andthen subsequently crystallizes. The crystals are filtered, washedseveral times with water and air dried.

COMPOSITIONS Compounds of this invention can be administered alone butare generally contained in a composition with an inert diluent non-toxicto animals. The diluent selected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of formula(1) to aid in dispersion of the active ingredient. Emulsifying agentsthat could be used include alkylaryl polyethoxy alcohols, alkyl andalkylaryl polyether alcohols, polyoxyethylene sorbitol or sorbitan fattyesters, polyethylene glycol fatty esters, fatty alkylol amidecondensates, amine salts of fatty alcohol sulfates plus long chainalcohols and oil soluble petroleum sulfonates.

The amount of emulsifying agent in the composition will range from 0.1to 20 percent by weight.

Since the compounds of the present invention would generally beadministered by vapor or spray application, the compositions willcontain a liquid diluent such as water, acetone, hexane, gasoline,kerosene, other hydrocarbon oils, alcohols or other liquids generallyused in pharmaceutical preparations.

The amount of active ingredient in the composition will vary from 0.005percent by weight to percent or even higher. The diluent will generallyconstitute the major proportion of the composition and the amount ofactive ingredient will be less than 50 percent by weight. The exactconcentration of the active ingredient will depend on the mechanism usedfor administration and will be easily understood by one knowledgeable inpharmaceutical application rates.

APPLICATION A quantity of active ingredient sufficient to causeirritation to animal tissue is to 10,000 micrograms per liter of air atexposure of one minute. It is expected that this rate applies to allanimals. Rates of over 10,000 micrograms per liter of air at exposure ofone minute kill 50 percent of the mice which are treated.

The following additional examples are provided to more particularlyexplain the invention.

EXAMPLE 1 A stirring solution of 14 grams (0.09 mole) of4-t-butylcyclohexylamine in 15 ml. of dimethylacetamide in a 50 ml.Erlenmeyer flask is treated with 29 grams (0.12 mole) of dichloroaceticanhydride. A vigorous, exothermic reaction occurs; the temperature isheld below 70C. during the addition by ice bath cooling. Thebrownish-yellow solution is stirred for 10 to 15 minutes, and then it ispoured into 500 ml. of water. The oil which separates crystallizes withscratching. The crystals are filtered, and washed with several 100 ml.portions of distilled water. TheN-dichloroacetyl-4t-butylcyclohexylamine is about a 1:1 cisztransmixture and melts from 120 to 129C. The yield is 23.9 grams (99 percentof theory).

Anal. Calc'd. for C H Cl NOz C, 54.1; H, 7.9; Cl, 26.6; N,

5.3 percent.

Found: C, 54.0; H, 7.8; C1, 26.3; N, 5.4 percent.

The cis/trans ratio of the product is determined on an F & M Model 500Gas Chromatograph using a 2 feet X 1/4 inch O.D. stainless steel columnpacked with percent Carbowax 20M on 60-80 mesh Diatoport T using acolumn temperature of 225C, an injection port temperature of 280C, ablock temperature of 312C.. and a helium flow rate of 60 cc./min. Thecis isomer has a retention time of 13.4 minutes, and the trans isomerhas a retention time of 22.8 minutes. The cis/trans ratio was 78/22.

In another experiment where the cis/trans ratio is 52/48, the productmelted from 135 to 145C.

The isomer mixture can be used for the purpose of this invention withoutseparation.

Mice are treated by aerosol exposure to this cis/trans mixture ofN-dichloroacetyl-4-t-butylcyclohexylamine in the following manner: Thecompound is administered as an aerosol into a 2.8 liter chamber. Theexposure chamber consists of a 2.8 liter bell jar over a nebullizerinserted through the floor of the chamber. Mice are exposed for fiveminutes to 600 micrograms per liter (3,000 Ct). The compound isdissolved in 1.4 ml. of acetone and during a span of 20 seconds thecompound is sprayed up into the chamber. No further air is transferredinto or out of the chamber during the five minute exposure.

After this exposure, irritant effects are observed in all mice exposed,but not in controls exposed to 1.4 ml. of acetone alone. lrritanteffects can be described as the presence of one or more of the followingreactive signs:

a. Lacrimation,

b. Abnormal gait,

c. Depression,

d. Dyspnea, and

e. Face pawing.

EXAMPLES 2-5 The following compounds are made in the manner of the N-dichloroacetyl-4-t-butylcyclohexylamine of Example 1 by substitutinglike molar amounts of the appropriate reactants for the 4-t-butylamineand dichloroacetic anhydride of Example 1. They produce similar irritanteffects upon administration to animals.

2. N-Dichloroacetyl-4-t-octylcyclohexylamine. 3.N-Dibromoacetyl-4-t-butylcyclohexylamine. 4. N-Dibromoacetyl-4-(1,1-dimethylbutyl)cyclohexylamine. 5. N-Dichloroacetyl-4-(l,1-dimethylhexyl)cyclohexylamine.

EXAMPLE 6 Pyridine (50 ml.) is treated with 19 grams (0.1 mole)chlorobromoacetyl chloride with stirring and cooling. The mixture isstirred for one-half hour and then grams (0.1 mole) of 4-t-butylamine isadded. The reactants are stirred for 1 hour and then the solution ispoured into 500 ml. of water. TheN-chlorobromoacetyl-4-t-butylcyclohexylamine separates as an oil whichsubsequently crystallizes. It is filtered, washed with water, and airdried.

This compound is formulated and applied in like amount of C, in a mannersimilar to N-dichloroacetyl-4-t-butylcyclohexylamine of Example 1 toprovide like results.

EXAMPLES 7-10 The following compounds are made in the manner of the N-chlorobromoacetyl-4-t-butylcyclohexylamine of Example 6 by substitutinglike molar amounts of the appropriate reactants for the 4-t-butylamineand the chlorobromoacetyl chloride. These compounds can be formulatedand applied in a manner similar to that given in Example 1 to producelike results.

7. N-Chlorobromoacetyl-4-t-octylcyclohexylamine. 8.N-Difluoroacetyl-4-t-butylcyclohexylamine.

9. N-Chlorobromoacety1-4-( l l ,3-trimethylpentyl)cyclohexylamine.

10. N-Methyl-N-dichloroacetyl-4-t-butylcyclohexylamine.

1 l. N-Dichloroacetyl-4-isopropylcyclohexylamine.

EXAMPLE 1 2 A 2 percent solution ofN-dichloroacetyl-4-t-butylcyclohexylamine in dichloromethane isdispersed into and through a chamber containing the test animals. Thisaerosol is generated by feeding the solution of test compound through acommercial paint sprayer jet at a rate of 10 ml./min., and dispersingthe spray with a stream of air having a flow rate of 44 liters/min.supplied at a pressure of 62 psi. The efficiency of forming respirableparticles ranges from 10 to 40 percent. This aerosol gives a chamberconcentration of 3.6 mg./liter; the particles have a mass mediandiameter of 1.6 microns with a geometric standard deviation of 2.6microns.

After young, adult, male guinea pigs are exposed to this aerosol for 1minute, lacrimation and salivation are observed. These irritant signspersist for one-half hour after the exposure.

When gerbils are exposed to this aerosol for one minute face pawing andtremors are observed. The face pawing persists for 5 minutes and thetremors persist for 10 minutes after the exposure.

lclaim:

1. Method of repelling animals comprising applying to an area to beprotected from these animals in an amount sufficient to cause irritationto animal tissue, a compound of the formula:

(1H, wherein R, is selected from the group consisting of hydrogen andalkyl of one through five carbon atoms;

R is selected from the group consisting of hydrogen and alkyl of onethrough three carbon atoms;

X is halogen; and

Z is halogen.

2. Method of repelling animals according to claim 1 wherein R, in thecompound to be applied is methyl.

3. Method of repelling animals according to claim 1 wherein X and Z inthe compound to be applied are chlorine.

4. Method of repelling animals according to claim 1 wherein R in thecompound to be applied is hydrogen.

5. Method of repelling animals according to claim 1 wherein R, is methyland R is hydrogen in the compound to be applied.

6. Method of repelling animals comprising applying to an area to beprotected from these animals in an amount sufficient to cause irritationto animal tissue, N-dichloroacetyl-4-tbutylcyclohexylamine.

7. Method of repelling animals comprising applying to an area to beprotected from these animals in an amount sufficient to cause irritationto animal tissue, N-chlorobromocetyl- 4-t-butylcyclohexylamine.

8. An animal irritant composition comprising a major amount of an inertliquid diluent non-toxic to animals and an amount sufficient to causeirritation to animal tissue of a compound of the formula:

wherein R, is selected from the group consisting of hydrogen and alkylof one through five carbon atoms; R is selected from the groupconsisting of hydrogen and alkyl of one through three carbon atoms;

X is halogen; and Z is halogen.

2. Method of repelling animals according to claim 1 wherein R1 in thecompound to be applied is methyl.
 3. Method of repelling animalsaccording to claim 1 wherein X and Z in the compound to be applied arechlorine.
 4. Method of repelling animals according to claim 1 wherein R2in the compound to be applied is hydrogen.
 5. Method of repellinganimals according to claim 1 wherein R1 is methyl and R2 is hydrogen inthe compound to be applied.
 6. Method of repelling animals comprisingapplying to an area to be protected from these animals in an amountsufficient to cause irritation to animal tissue,N-dichloroacetyl-4-t-butylcyclohexylamine.
 7. Method of repellinganimals comprising applying to an area to be protected from theseanimals in an amount sufficient to cause irritation to animal tissue,N-chlorobromocetyl-4-t-butylcyclohexylamine.
 8. An animal irritantcomposition comprising a major amount of an inert liquid diluentnon-toxic to animals and an amount sufficient to cause irritation toanimal tissue of a compound of the formula: